Cancer claims over six million lives each year worldwide and is the largest single cause of death in both men and women. Extrinsic factors, including personal lifestyles, play a major role in the development of most human malignancies. Cigarette smoking, consumption of alcohol, exposure to synthetic and naturally occurring carcinogens, radiation, drugs, infectious agents, and reproductive and behavioral practices are widely recognized as important contributors to the etiology of cancer.
A surprising conclusion is that the human diet plays a causative role in more than one-third of human neoplasia. However, the human diet not only contains numerous mutagens and carcinogens, but also contains a variety of chemicals that block carcinogenesis in animal models. Chemoprevention, i.e., the prevention, delay, or reversal of carcinogenesis through ingestion of dietary or pharmaceutical agents, therefore, is one of the most direct ways to reduce cancer-related morbidity and mortality. See, M. B. Sporn, Fed. Proc., 38, 2528 (1979).
Dietary modifications can modulate cancer risk in various ways. For example, changes in caloric intake, altering the consumption of nutritive and nonnutritive diet components, and providing exposure to numerous minor chemicals that may be genotoxic or protective can increase or decrease the risk of cancer. Modifying the human diet to reduce the risk of cancer requires the identification of dietary carcinogens and chemopreventatives, even though interactions between the factors that modulate cancer risk are complex. Whereas extensive efforts have been made to identify dietary carcinogens and mutagens, the identification of chemopreventative agents has received less attention.
A large number of potential chemopreventive agents are known, some of which have proven effective in clinical trials. These agents function in a variety of mechanisms, and are directed at all major stages of carcinogenesis.
Cancer chemopreventive agents include nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin, aspirin, piroxicam, and sulindac, all of which inhibit cyclooxygenase, abbreviated hereafter as COX. COX inhibitory activity is important in cancer chemoprevention because COX catalyzes the conversion of arachidonic acid to proinflammatory substances, such as prostaglandins, which can stimulate tumor cell growth and suppress immune surveillance. O. J. Plescia et al., Proc. Natl. Acad. Sci. U.S.A., 72, 1848 (1975), and J. S. Goodwin, Am. J. Med., 77, 7 (1984). In addition, COX can activate carcinogens to forms that damage genetic material. T. V. Zenser et al., J. Pharmacol. Exp. Ther., 227, 545 (1983), and D. Wild et al., Carcinogenesis, 8, 541 (1987).
Another promising pathway for preventing chemical-induced carcinogenesis is to alter tumor initiation through the induction of phase II detoxification enzymes and the elevation of intracellular glutathione (GSH) levels. Phase II enzymes, such as quinone reductase (QR) and glutathione S-transferase (GST), are a group of inducible enzymes responsible for facilitating the removal of xenobiotics from animals and humans. QR protects cells against the cytotoxicity of quinones by promoting obligatory two-electron reductions of quinones, thereby preventing their participation in oxidative cycling and interaction with critical nucleophilies. GST detoxifies by catalyzing the conjugation of GSH to various reactive electrophiles which decrease the availability of reactive electrophiles to bind to DNA and possibly initiate the transformation process. GSH, as the principal intracellular nonprotein thiol compound, functions as cosubstrate for GST-catalysed conjugation of electrophilic chemicals. Chemopreventive activity of phase II enzyme inducers can be achieved by modification of carcinogen metabolism, increasing carcinogen excretion, and decreasing carcinogen DNA interactions.
Several chemopreventive compounds have been identified solely on the basis of their ability to induce phase II enzymes in laboratory animals and cell cultures. Similarly, during our study directed to identifying novel chemopreventive compounds, cultured Hepa 1c1c7 cells were used to evaluate the potential of compounds to enhance QR activity. This study led to the identification of various active agents, including brassinin, withanolides, and sulforamate. In addition, as exemplified by our work with Tephrosia purpurea, some novel flavonoids were found to act as potent phase II enzyme inducers.
Compounds that induce phase II detoxification enzymes have been shown to protect against carcinogen-initiated cancer. Inducers of phase I enzymes, such as cytochrome P450 isozymes, are required for metabolic disposal of xenobiotics, but also are considered a cancer risk factor because of their potential to activate procarcinogens and increase the carcinogenicity of various compounds. Evidence of phase I induction of cytochrome P-4501A1 isozyme by 4'-bromoflavone was disclosed in Y. F. Lu et al., Biochemical Pharmacology, 51, pages 1077-1087, (1996).
Compounds that elevate phase I and phase II enzymes are classified as bifunctional inducers. Monofunctional inducers selectively elevate phase II enzymes. Sulforaphane, a compound isolated from broccoli, was reported as the most potent monofunctional inducer of phase II enzymes, but the compound is toxic, and difficult and very expensive to synthesize. Cho et al. U.S. Pat. No. 5,411,986 discloses several analogs of sulforaphane that induce phase II enzymes and may be useful as chemoprotective agents. Han et al. U.S. Pat. No. 5,703,130 discloses chalcone retinoids having biological activity on cancer or precancer cells. Briet et al. U.S. Pat. No. 5,116,954 discloses flavonic compounds having anticancer activity.
There still is a need in the art, however, for the identification of compounds that have a cancer chemopreventative effect on mammals. Such cancer chemopreventative compounds then can be used in drug compositions or as food additives to reduce the risk of cancer. To this end investigators have searched for new cancer chemopreventative agents by evaluating hundreds of plant extracts for a potential to induce phase II enzymes. There also is a need to find synthetic chemopreventative compounds having a low toxicity, and that can be synthesized easily and economically to provide useful amounts of the compounds.